MiR-199a family members are differentially regulated during physiological and pathological cardiac hypertrophy.

Among potential molecular mechanisms supporting cardiovascular homeostasis, miRNAs (miRs) represent interesting candidates. We recently highlighted that miR-199a controls the Nitric oxide synthase/nitric oxide (NOS/NO) pathway in the endothelium and showed that both mature strands of miR-199a are overexpressed in heart and vessels from a mouse model of hypertension. Here we investigated the fate of miR-199a in heart and vessels from mice developing physiological or pathological cardiac hypertrophy. Our working hypothesis is that alterations in cell phenotypes driven by changes in miR-199a abundance account for cardiac and/or vascular adaptation to increased workload in patho-physiological contexts. C57BL/6J mice were given access to voluntary dynamic wheel training during 22 weeks or underwent transverse aortic constriction (TAC) surgery. As a result, those mice respectively developed physiological and pathological cardiac hypertrophy. An opposite modulation of miR-199a-3p and miR-199a-5p expression was observed in vessels and heart from running vs TAC mice which correlated with opposite regulation of Retinobastoma1 (RB1) in cardiac tissue. We show that miR-199a-3p upregulation, by indirectly modulating CCAAT/enhancer binding protein (C/EBP)β, promotes cardiomyocyte hypertrophy in the pathological settings, while its repression by exercise drives metabolic adaptations associated with physiological remodeling. Interestingly, miR-199a-5p repression also directly target Sirtuin 1 (Sirt-1) and Peroxisome proliferator-activated receptor coactivator (PGC1)α Taken together, our findings indicate that both mature arms of miR-199a act in tandem to drive morphologic and metabolic adaptations encountered in physiological and pathological cardiac hypertrophy.